Type 1 diabetes (T1D) is an inflammatory disease of the pancreatic islets that afflicts millions of people worldwide. Although the etiological factors that trigger the disease vary, the common pathological outcome of T1D is the destruction of insulin-producing p cells by inflammatory cells through a process called insulitis. Development of insulitis requires coordinated expression of a large number of genes that mediate the activation, migration and effector functions of inflammatory cells. These include genes that encode cytokines, chemokines, and cytotoxic enzymes. While it is well recognized that expression of these genes is tightly regulated at the transcriptional level, the nature of the transcription factors involved and the mechanisms of their action in T1D are not well understood. Recent studies from several laboratories including ours indicate that the nuclear factor (NF)-KB family of transcription factors plays crucial roles in T1D. Thus, in both mice and humans, T1D is associated with heightened NF-icB activation, whereas NF-KB deficiency in mice renders them resistant to the disease. Importantly, inhibiting NF-KB activities is highly effective in suppressing models of T1D. Therefore, NF-icB has emerged as a long sought-after transcriptional regulator of T1D. However, NF-icB is expressed not only by lymphoid and myeloid cells that cause insulitis, but also by cells of the non-immune systems including p cells of the pancreatic islets that are destroyed by insulitis. NF-KB-based therapeutic strategies would be most effective if they selectively target those cells or NF-xB pathways that are directly responsible for the pathogenesis of T1D. We hypothesize that NF-KB expressed by different cell types activates different sets of genes and plays different roles in T1D: NF-KB expressed by inflammatory cells orchestrates their activation and effector function by activating pro-\ inflammatory genes whereas NF-KB expressed by pancreatic /3cells regulates their death and survival by activating apoptotic genes. The specific aims of this proposal are: 1) To test the hypothesis that NF-KB expressed by lymphoid and myeloid cells promotes type 1 diabetes by activating pro-inflammatory genes. 2) To test the hypothesis that NF-KB expressed by pancreatic (3cells dictates their fate in type 1 diabetes by activating apoptotic genes. 3) To test the hypothesis that the NF-KB-IL-23 axis plays a key role in the pathogenesis of type 1 diabetes. 4) To treat type 1 diabetes by blocking inducible NF-KB activity. Information generated from the proposed studies will help establish which cell(s) and which NF-KB pathway(s) should be selectively targeted for the treatment of T1D. A new class of NF-KB inhibiting drugs may then be developed to treat T1D.